RGD Reference Report - Synergistic activation of glucose-6-phosphate dehydrogenase and NAD(P)H oxidase by Src kinase elevates superoxide in type 2 diabetic, Zucker fa/fa, rat liver. - Rat Genome Database

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Synergistic activation of glucose-6-phosphate dehydrogenase and NAD(P)H oxidase by Src kinase elevates superoxide in type 2 diabetic, Zucker fa/fa, rat liver.

Authors: Gupte, RS  Floyd, BC  Kozicky, M  George, S  Ungvari, ZI  Neito, V  Wolin, MS  Gupte, SA 
Citation: Gupte RS, etal., Free Radic Biol Med. 2009 Feb 20.
RGD ID: 2307340
Pubmed: PMID:19230846   (View Abstract at PubMed)
PMCID: PMC2700195   (View Article at PubMed Central)
DOI: DOI:10.1016/j.freeradbiomed.2009.01.028   (Journal Full-text)

Glucose metabolism through the glycolysis and hexosamine pathway has been shown to be altered in type 2 diabetes. However, the fate of glucose through the pentose phosphate pathway (PPP) is currently unclear. In this study, we determined whether the activity of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the PPP, is modulated in the liver of Zucker obese fa/fa rats (9-11 weeks of age). We found that G6PD expression and activity, NADPH levels, and 6-phosphogluconate generation were significantly increased in the liver of fa/fa rats. Inhibition of PI3 kinase and Src kinases decreased (p<0.05) G6PD activity in the fa/fa but not in the lean rat liver, suggesting that G6PD activity is regulated by PI3/Src kinase signaling pathways. G6PD-derived NADPH increased (p<0.05) superoxide anion levels by 70-90% in fa/fa vs lean rat liver, which was inhibited by the NADPH oxidase inhibitor gp91(ds-tat) (50 muM) and G6PD inhibitors 6-aminonicotinamide (1 mM) and dehydroepiandrosterone (100 muM), therefore indicating that elevated G6PD activity may be responsible for mediating superoxide generation. Interestingly, we also found a positive correlation between liver hypertrophy/increased G6PD activity (r(2)=0.77; p=0.0009) and liver hypertrophy/superoxide production (r(2)=0.51; p=0.0091) in fa/fa rats. Increased G6PD and NADPH oxidase expression and activity, in young hyperglycemic and hyperinsulinemic rats before the development of diabetes, seems to be a contributing factor in the induction of oxidative stress. Because inhibition of G6PD activity decreases oxidative stress, we conclude that G6PD behaves as a pro-oxidant in the fa/fa rat liver in type 2 diabetes.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
obesity  ISOG6pd (Rattus norvegicus)2307340; 2307340associated with Diabetes Mellitus more ...RGD 
obesity  IEP 2307340associated with Diabetes Mellitus more ...RGD 
type 2 diabetes mellitus  ISOSrc (Rattus norvegicus)2307340; 2307340 RGD 
type 2 diabetes mellitus  IMP 2307340 RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
positive regulation of glucose metabolic process  IMP 2307340 RGD 

Objects Annotated

Genes (Rattus norvegicus)
G6pd  (glucose-6-phosphate dehydrogenase)
Src  (SRC proto-oncogene, non-receptor tyrosine kinase)

Genes (Mus musculus)
G6pdx  (glucose-6-phosphate dehydrogenase X-linked)
Src  (Rous sarcoma oncogene)

Genes (Homo sapiens)
G6PD  (glucose-6-phosphate dehydrogenase)
SRC  (SRC proto-oncogene, non-receptor tyrosine kinase)


Additional Information